Essential oils have been used for their bioactivity for quite some time. Some essential oils are currently being used as medicaments. For example the plants mentha piperita or mentha arvensis, are the two primary sources of peppermint oil. Peppermint oil is effective at treating the symptoms of gastrointestinal disorders such as irritable bowel syndrome (IBS), functional dyspepsia (FD), gastro paresis (GP), Crohn's disease (CD) and ulcerative colitis (UC). These symptoms can include pain, discomfort, bloating, constipation, and/or diarrhea. Clinical trials have demonstrated significant alleviation of the symptoms associated with IBS through the use of peppermint oil in single-unit capsules coated with the cellulose acetate-phthalate enteric polymer or other enteric-coating polymers.
For maximal efficacy in the treatment of IBS, FD, GP, CD and UC, and to avoid related complications, peppermint oil should be locally delivered to various sections of the intestines (i.e. duodenum, small intestine, ileum or large intestine [i.e. colon]), while avoiding the stomach. If peppermint oil is released from its dosage form prior to passing through the pyloric sphincter into the intestines, it can irritate the mucous membranes in the upper digestive tract. Releasing peppermint oil directly into the stomach can cause heartburn (gastric irritation) and gastro-esophogeal reflux disease. Therefore, since peppermint oil is usually administered orally, it should preferably be prepared with an enteric coating.
Enteric-coated single-unit capsules for treating irritable bowel syndrome and functional dyspepsia that contain peppermint oil currently exist. But, even though the enteric coated single-unit capsules are meant to delay the release of peppermint oil until after the capsule enters the intestines, this approach to treating gastrointestinal (GI) disorders has several drawbacks. The drawbacks include premature release of the peppermint oil from the capsule in the stomach, resulting in heartburn. Also, accidental chewing of the capsule causes the enteric coat to rupture prematurely and release the oil in the stomach.
The oil that is released from single-unit capsules is typically dissolved in cooking oil (such as peanut oil) to modify its release in the intestines. The peppermint oil (dissolved in cooking oil) released from single unit capsules, does not dissolve in the aqueous contents of the stomach but forms a layer of oil which floats on top of the aqueous phase in the stomach. This increase the likelihood of the peppermint oil plus cooking oil regurgitating into the esophageal area and causing reflux.
Using current formulations of peppermint oil, significant doses are required to achieve an efficacious concentration of peppermint oil in the body. For example, each of the above referenced capsules contains about 200 mg of peppermint oil and must be taken three times a day, 30-60 minutes prior to a meal. The dose can be increased to two capsules taken three times daily in some situations.
Enteric-coated peppermint oil is typically administered as a single-unit capsule formulation. However, in a single-unit formulation, the amount of peppermint oil absorbed by the intestines can vary from dose to dose for several reasons. First, single-unit enteric capsule formulation can get attached to the esophagus because of the muco-adhesive properties of the enteric coat and, therefore, not enter the stomach within the desired time frame. The single-unit enteric coated capsules, like enteric coated single-unit tablets, have been shown to not release the active ingredient from the single-unit formulation because the single-unit's size is too large to pass through the constriction in the stomach's pylorus valve, until the inter-digestive or house cleaning phase. The enteric coat of the capsule may also prematurely crack or rupture because of the force created by the swelling of the gelatin or hypromellose used to form the capsule shell due to its water of hydration, against the outer enteric coat. Because peppermint oil containing capsules have a lower specific gravity than the stomach contents, they tend to float rather than settle and pass through the pylorus constriction between the stomach and the lower intestines, unreliably and only during the inter-digestive phase.
Non-disintegrating tablets or capsules given with food may stay in the stomach for long times, up to 10 to 15 hours, before they are emptied into the small intestine. Small particles, with diameters less than or about 3 mm, are emptied from the stomach more regularly, regardless of whether they are given with food. The 10 to 15 hours that an enteric coated hard gelatin or hypromellose capsule may get exposure to gastric conditions in a fed state may cause the enteric coat to rupture and the hard gelatin (or hypromellose) seal coat to dissolve, resulting in the peppermint oil being released in the stomach and causing heartburn or gastric irritation.
Even if the single-unit enteric coated capsule passes through the pylorus intact in a timely fashion, when it reaches the small intestine, the coating dissolves and a bolus of oil is released. This dosage dumping is a situation in which the active ingredient is released and gives very high local exposure in a segment of the intestine, is also undesirable because it prevents uniform and steady exposure of peppermint oil in the GI lumen. This high local exposure to one section of the GI lumen may actually aggravate symptoms of IBS.
Single-unit formulations are also significantly influenced by the presence of food in the stomach. Gastric emptying rates of single-unit doses are erratic and unpredictable. Single-unit enteric-coated tablets or capsules taken with food may stay in the stomach for many hours before being emptied into the small intestine. As a result, single-unit formulations present both high inter and intra-subject variability with respect to the pharmacokinetics (PK) and local bioavailable concentration of active ingredient. According to regulatory guidelines, enteric-coated single-unit capsules can never be bioequivalent with multiple-unit enteric-coated dosage forms. A single-unit enteric preparation containing peppermint oil was disclosed in U.S. Pat. No. 4,687,667.
The currently available delayed release single-unit dosage forms containing enteric-coated peppermint oil have another limitation. They dump their primary active ingredient, L-menthol, when the enteric layer disintegrates. The terminal half-life of L-menthol is ˜1.34 hours. Therefore, the systemic exposure of L-menthol is limited to approximately 4 hours, resulting in the need for frequent dosing (usually three times a day) to relieve the symptoms of IBS. The peppermint oil is usually dissolved in cooking oil to slow the release of L-menthol into the aqueous phase. However, cooking oil can aggravate the symptoms of IBS and the rate of release from the cooking oil is dependent on the diameter of the droplets of the oil. The diameter of the oil droplets is controlled by the presence of surfactants (bile acids etc.) and other oily substances in the stomach. With a multiparticulate delivery system, the individual particles pass through the pylorus over a longer period (approximately 90 minutes) and release their content steadily over this time period. The use of a single-unit non-disintegrating delayed release dosage form is undesirable because they release (dump) their active ingredient immediately after the single unit's enteric layer is dissolved.
In U.S. patent publication 2012/0207842, we described enteric coated multiparticulate L-menthol compositions adapted to overcome the drawbacks associated single-unit dosage forms. In order to prevent the L-menthol from sublimating as the cores were being processed, we resorted to low temperature processing techniques. The L-menthol multiparticulate compositions described in that application provided the release profile that we desired and worked well for some applications, but were not optimized for all applications.
We have identified a need for a multiparticulate L-menthol-containing formulation that avoids the drawbacks associated with single-unit enteric coated capsules and can be made using conventional room temperature processing techniques